Zinc-Related Proteasome Variants in Type 1 Diabetes: An in Silico-Guided Case-Control Study

The proteasome is a multicatalytic complex responsible for protein degradation and regulation of immune responses, and has been implicated in type 1 diabetes mellitus (T1DM) pathogenesis. Zinc (Zn²⁺) is essential for insulin granule biogenesis and modulates proteasomal activity. This study investigated associations between single-nucleotide polymorphisms (SNPs) in proteasomal subunits predicted to bind Zn²⁺ and T1DM susceptibility or related traits.

This case-control study included 654 patients with T1DM and 573 subjects without DM from Southern Brazil. SNPs were selected through in silico analysis using MIB docking platform to identify Zn²⁺-interacting residues in proteasomal subunits. Five SNPs in proteasomal subunit genes-PSMA6 (rs1048990), PSMB6 (rs2304975), PSMB9 (rs17587), PSMC6 (rs2295825), and PSMD3 (rs3087852)-were genotyped using TaqMan assays.

The PSMC6 rs2295825C allele was associated with lower T1DM (OR = 0.77, 95% CI 0.61-0.97; p = 0.028) and diabetic retinopathy (DR; OR = 0.65; 95% CI 0.42-0.99; p = 0.048) risk, and a more favorable lipid profile (higher HDL-C, lower triglycerides) compared to the G/G genotype. The PSMB9 rs17587A/A genotype was linked to higher total cholesterol and HbA1c levels. The PSMA6 rs1048990G allele was linked to increased prevalence of diabetic kidney disease (DKD; OR = 1.75, 95% CI 1.02-2.99; p = 0.042), and the PSMD3 rs3087852A allele was associated with lower urinary albumin excretion. No significant associations were observed for the PSMB6 rs2304975 SNP.

The PSMC6 rs2295825 SNP may confer protection against T1DM. The PSMC6 rs2295825, PSMB9 rs17587, PSMA6 rs1048990, and PSMD3 rs3087852 SNPs appear to influence lipid metabolism and diabetic microvascular complications.